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Association of mammographic density with the proliferation marker Ki-67 in a cohort of patients with invasive breast cancer

  • Epidemiology
  • Published:
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Abstract

There is growing evidence that certain breast cancer (BC) risk factors specifically increase the risk for specific molecular tumor subtypes. Different molecular subtypes of BC can partly be described by analyzing proliferation in tumors. Very few data are available regarding the association of mammographic density (MD), as a BC risk factor, with proliferation. The aim of this study was to analyze the association between Ki-67 expression in BCs and MD. In this case-only study, data on BC risk factors, hormone receptor expression, and MD were available for 1,975 patients with incident BC. MD was assessed as percentage mammographic density (PMD) using a semiautomated method by two readers for every patient. The association of the Ki-67 proliferation index and PMD was studied using multifactorial analyses of covariance (ANCOVA), with PMD as the target variable and including well-known factors that are also associated with MD such as age, parity, use of hormone replacement therapy (HRT), and body mass index (BMI). There were no significant differences in PMD between women with BC who had low and high Ki-67 values (P = 0.31). However, there were relevant differences in women with low BMI (P = 0.07), and in women using postmenopausal HRT (P = 0.06) as well as in women with low PR values (P = 0.07). In these subgroups, the Ki-67 expression index increased with decreasing PMD. Likewise PMD is correlated with BMI, parity status, and menopausal status stronger in patients with low proliferating tumors, and with progesterone receptor expression in patients with high proliferating tumors. MD correlates inversely with Ki-67 proliferation in BC tumors only in some subgroups of BC patients, defined by commonly known BC risk factors that are usually associated with MD as well.

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References

  1. Liedtke C, Wolf MK, Kiesel L (2010) New concepts for targeted systemic therapy in breast cancer. Geburtsh Frauenheilkd 70(8):625–633. doi:10.1055/s-0030-1250182

    Article  Google Scholar 

  2. Fasching PA, Ekici AB, Adamietz B et al (2011) Breast cancer risk—genes, environment, and clinical practice. Geburtsh Frauenheilkd 71(12):1056–1066. doi:10.1055/s-0031-1280437

    Article  CAS  Google Scholar 

  3. Yerushalmi R, Woods R, Ravdin PM et al (2010) Ki67 in breast cancer: prognostic and predictive potential. Lancet Oncol 11(2):174–183. doi:10.1016/S1470-2045(09)70262-1

    Article  PubMed  CAS  Google Scholar 

  4. Dowsett M, Nielsen TO, A’Hern R et al (2011) Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst 103(22):1656–1664. doi:10.1093/jnci/djr393

    Article  PubMed  CAS  Google Scholar 

  5. Paik S, Shak S, Tang G et al (2004) A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351(27):2817–2826. doi:10.1056/NEJMoa041588

    Article  PubMed  CAS  Google Scholar 

  6. Cuzick J, Dowsett M, Pineda S et al (2011) Prognostic value of a combined estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the Genomic Health recurrence score in early breast cancer. J Clin Oncol 29(32):4273–4278. doi:10.1200/JCO.2010.31.2835

    Article  PubMed  Google Scholar 

  7. Sotiriou C, Pusztai L (2009) Gene-expression signatures in breast cancer. N Engl J Med 360(8):790–800. doi:10.1056/NEJMra0801289

    Article  PubMed  CAS  Google Scholar 

  8. Cheang MC, Chia SK, Voduc D et al (2009) Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 101(10):736–750. doi:10.1093/jnci/djp082

    Article  PubMed  CAS  Google Scholar 

  9. Fasching PA, Heusinger K, Haeberle L et al (2011) Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment. BMC Cancer 11:486. doi:10.1186/1471-2407-11-486

    Article  PubMed  CAS  Google Scholar 

  10. Phipps AI, Chlebowski RT, Prentice R et al (2011) Reproductive history and oral contraceptive use in relation to risk of triple-negative breast cancer. J Natl Cancer Inst 103(6):470–477. doi:10.1093/jnci/djr030

    Article  PubMed  Google Scholar 

  11. Yang XR, Chang-Claude J, Goode EL et al (2011) Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies. J Natl Cancer Inst 103(3):250–263. doi:10.1093/jnci/djq526

    Article  PubMed  Google Scholar 

  12. Stacey SN, Manolescu A, Sulem P et al (2008) Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 40(6):703–706. doi:10.1038/ng.131

    Article  PubMed  CAS  Google Scholar 

  13. Stacey SN, Manolescu A, Sulem P et al (2007) Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 39(7):865–869. doi:10.1038/ng2064

    Article  PubMed  CAS  Google Scholar 

  14. Garcia-Closas M, Chanock S (2008) Genetic susceptibility loci for breast cancer by estrogen receptor status. Clin Cancer Res 14(24):8000–8009. doi:10.1158/1078-0432.CCR-08-0975

    Article  PubMed  CAS  Google Scholar 

  15. Garcia-Closas M, Hall P, Nevanlinna H et al (2008) Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. PLoS Genet 4(4):e1000054. doi:10.1371/journal.pgen.1000054

    Article  PubMed  Google Scholar 

  16. Thomas G, Jacobs KB, Kraft P et al (2009) A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nat Genet 41(5):579–584. doi:10.1038/ng.353

    Article  PubMed  CAS  Google Scholar 

  17. Turnbull C, Ahmed S, Morrison J et al (2010) Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet 42(6):504–507. doi:10.1038/ng.586

    Article  PubMed  CAS  Google Scholar 

  18. Ahmed S, Thomas G, Ghoussaini M et al (2009) Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nat Genet 41(5):585–590. doi:10.1038/ng.354

    Article  PubMed  CAS  Google Scholar 

  19. Broeks A, Schmidt MK, Sherman ME et al (2011) Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium. Hum Mol Genet 20(16):3289–3303. doi:10.1093/hmg/ddr228

    Article  PubMed  Google Scholar 

  20. Antoniou AC, Beesley J, McGuffog L et al (2010) Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction. Cancer Res 70(23):9742–9754. doi:10.1158/0008-5472.CAN-10-1907

    Article  PubMed  CAS  Google Scholar 

  21. Antoniou AC, Wang X, Fredericksen ZS et al (2010) A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population. Nat Genet 42(10):885–892. doi:10.1038/ng.669

    Article  PubMed  CAS  Google Scholar 

  22. Stevens KN, Vachon CM, Lee AM et al (2011) Common breast cancer susceptibility loci are associated with triple-negative breast cancer. Cancer Res 71(19):6240–6249. doi:10.1158/0008-5472.CAN-11-1266

    Article  PubMed  CAS  Google Scholar 

  23. McCormack VA, dos Santos SI (2006) Breast density and parenchymal patterns as markers of breast cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev 15(6):1159–1169. doi:10.1158/1055-9965.EPI-06-0034

    Article  PubMed  Google Scholar 

  24. Boyd NF, Guo H, Martin LJ et al (2007) Mammographic density and the risk and detection of breast cancer. N Engl J Med 356(3):227–236. doi:10.1056/NEJMoa062790

    Article  PubMed  CAS  Google Scholar 

  25. Heusinger K, Loehberg CR, Haeberle L et al (2011) Mammographic density as a risk factor for breast cancer in a German case–control study. Eur J Cancer Prev 20(1):1–8. doi:10.1097/CEJ.0b013e328341e2ce

    Article  PubMed  Google Scholar 

  26. Yaghjyan L, Colditz GA, Collins LC et al (2011) Mammographic breast density and subsequent risk of breast cancer in postmenopausal women according to tumor characteristics. J Natl Cancer Inst 103(15):1179–1189. doi:10.1093/jnci/djr225

    Article  PubMed  Google Scholar 

  27. Heusinger K, Jud SM, Haberle L et al (2012) Association of mammographic density with hormone receptors in invasive breast cancers—results from a case-only study. Int J Cancer. doi:10.1002/ijc.27515

  28. Aiello EJ, Buist DS, White E et al (2005) Association between mammographic breast density and breast cancer tumor characteristics. Cancer Epidemiol Biomarkers Prev 14(3):662–668. doi:10.1158/1055-9965.EPI-04-0327

    Article  PubMed  Google Scholar 

  29. Fasching PA, Heusinger K, Loehberg CR et al (2006) Influence of mammographic density on the diagnostic accuracy of tumor size assessment and association with breast cancer tumor characteristics. Eur J Radiol 60(3):398–404. doi:10.1016/j.ejrad.2006.08.002

    Article  PubMed  Google Scholar 

  30. Beckmann MW, Brucker C, Hanf V et al (2011) Quality assured health care in certified breast centers and improvement of the prognosis of breast cancer patients. Onkologie 34(7):362–367. doi:10.1159/000329601

    Article  PubMed  Google Scholar 

  31. Ursin G, Astrahan MA, Salane M et al (1998) The detection of changes in mammographic densities. Cancer Epidemiol Biomarkers Prev 7(1):43–47

    PubMed  CAS  Google Scholar 

  32. Blamey RW, Cataliotti L (2006) EUSOMA accreditation of breast units. Eur J Cancer 42(10):1331–1337. doi:10.1016/j.ejca.2006.04.003

    Article  PubMed  CAS  Google Scholar 

  33. Verheus M, Maskarinec G, Erber E et al (2009) Mammographic density and epithelial histopathologic markers. BMC Cancer 9:182. doi:10.1186/1471-2407-9-182

    Article  PubMed  Google Scholar 

  34. Perou CM, Sorlie T, Eisen MB et al (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752. doi:10.1038/35021093

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Katharina Heusinger was funded by the ELAN Program at Erlangen University Hospital, Friedrich Alexander University of Erlangen-Nuremberg, Germany. We are grateful to Michael Robertson for professional medical editing services.

Conflict of interest

The authors hereby declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Gynecology and Obstetrics, University Breast Center for Franconia, Erlangen University Hospital, Friedrich Alexander University of Erlangen–Nuremberg, Erlangen, Germany

    Katharina Heusinger, Sebastian M. Jud, Lothar Häberle, Carolin C. Hack, Peter A. Fasching, Michael P. Lux, Carsten Hagenbeck, Christian R. Loehberg, Claudia Rauh & Matthias W. Beckmann

  2. Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA

    Peter A. Fasching

  3. Institute of Radiology, University Breast Center for Franconia, Erlangen University Hospital, Friedrich Alexander University of Erlangen–Nuremberg, Erlangen, Germany

    Martina Meier-Meitinger, Michael Uder & Rüdiger Schulz-Wendtland

  4. Fraunhofer Institute for Integrated Circuits IIS, Erlangen, Germany

    Thomas Wittenberg & Florian Wagner

  5. Erlangen–Nuremberg Comprehensive Cancer Center, Erlangen, Germany

    Katharina Heusinger, Sebastian M. Jud, Lothar Häberle, Carolin C. Hack, Peter A. Fasching, Michael P. Lux, Carsten Hagenbeck, Christian R. Loehberg & Matthias W. Beckmann

  6. Institute of Pathology, Erlangen University Hospital, Friedrich Alexander University of Erlangen–Nuremberg, Erlangen, Germany

    Arndt Hartmann & David L. Wachter

Authors
  1. Katharina Heusinger
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  2. Sebastian M. Jud
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  3. Lothar Häberle
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  4. Carolin C. Hack
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  5. Peter A. Fasching
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  7. Michael P. Lux
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  8. Carsten Hagenbeck
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  9. Christian R. Loehberg
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  10. Thomas Wittenberg
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  12. Florian Wagner
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  13. Michael Uder
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  14. Arndt Hartmann
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  15. Rüdiger Schulz-Wendtland
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  16. Matthias W. Beckmann
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Corresponding author

Correspondence to Peter A. Fasching.

Additional information

Katharina Heusinger and Sebastian M. Jud contributed equally to this study.

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Heusinger, K., Jud, S.M., Häberle, L. et al. Association of mammographic density with the proliferation marker Ki-67 in a cohort of patients with invasive breast cancer. Breast Cancer Res Treat 135, 885–892 (2012). https://doi.org/10.1007/s10549-012-2221-3

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  • DOI: https://doi.org/10.1007/s10549-012-2221-3

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